1. Field of the Invention
The present invention concerns the field of adenoviral ocular and genital infections and in particular a composition and method for their treatment and prevention.
2. Description of the Related Art
Adenoviruses belong to the group of polyhedral DNA-viruses and are characterised by their icosahedral capsid shell with 20 identical faces and an overall hexagonal shape. In adenoviruses, the capsid is naked, meaning that it does not have the lipid membrane envelope common to many other viruses. This fact may partly explain its resistance to most disinfecting agents and its ability to withstand desiccation.
Adenoviruses afflicting man exhibit 51 different serotypes, which can be divided in six groups depending on the different symptoms. The tropism of the six subgenera A through F is suggested to be directed by differences in the structure of the adenovirus fibre. The adenovirus fibre has specificity for the cellular coxsackie adenovirus receptor (CAR), which is also called the first step receptor. It was therefor surprising when it was demonstrated that representative adenoviruses of subgenus A, C, D, E and F all were demonstrated to bind to CAR.
In a virus particle it is the hexon, penton bases and fibres which initially interact with a susceptible cell. The capsid proteins also interact with the immune system of the infected host. Adenoviruses bind to the first step receptor through the distal part of the fibre—the fibre knob. The charge of this globular structure—having 174-191 amino acid residues—varies between 4.5 to 9.1 in their isoelectric points.
The internalisation step probably involves a second receptor-ligand interaction. The ligand is the variable portion of the adenovirus vertex capsomer and the receptor on the host cell is alpha-v-integrin heterodimers.
Group D is known to cause genital and ocular infections, the latter either engaging the conjunctiva (conjunctivitis) or, in more severe infections, engaging also the cornea (keratoconjunctivitis). Adenoviral ocular infections are known to occur world-wide in community- and office-based epidemics. The main routes of transmission are believed to be direct contact eye-to-hand-to-eye or secondary eye-to-hand-to-hand-to-eye. Also sexual transmission occurs. Other sources of infection are believed to be swimming pools, eye clinics or ophthalmology departments.
Obviously densely populated areas are more prone to epidemic spread of diseases and consequently several epidemics have been observed in Asian countries during the last decade. Terminating established epidemics can be difficult. There are examples of eye clinic or ophthalmology department based epidemics that have taken several months to eradicate completely.
Outbreaks of keratitis are mainly caused by the following adenovirus sero-types; Ad8, Ad19, Ad37 and Ad4, in addition to Herpes virus type 1. On the other hand, conjunctivitis is mainly caused by Ad3, Ad4 and Ad7, but also by Enterovirus 70 and by other adenoviruses.
Antiviral compounds have been developed for the treatment of ocular infections, where Herpes viruses are the causative agent or agents. Attempts to treat adenoviral ocular infections with topical antiherpetic antivirals have been unsuccessful. Therefore the presently applied therapy aims at alleviating the symptoms and limiting the spread of the disease. Alleviating treatments include cold compresses, dark glasses, vasoconstrictors and, although not generally accepted, cyclosporin A and corticosteroids. The use of antibiotics and corticosteroids, either separately or in combination, has not been proven to be effective and, furthermore, is associated with the risk of possible side-effects.
For an overview of adenovirus associated ocular infections, see Gordon et al., Adenovirus Keratoconjunctivitis, in Ocular Infection and Immunology, Ed, J. S. Pepsose Mosby, 1996, pages 877-894.